The Chronic Rhinosinusitis Integrative Studies Program 2 (CRISP2) is an integrated program of epidemiologists, otolaryngologists, allergists and immunologists with highly collaborative studies to better understand the molecular and cellular mechanisms of disease heterogeneity and how these mechanisms translate into clinical phenotypes, natural history and long term outcomes. There is a compelling need for more research in chronic rhinosinusitis (CRS). Patients with CRS experience a dramatic decrement in quality of life, CRS has a prevalence approaching 12%, nearly half a million patients per year undergo surgery and the estimated total costs of CRS in the US are $22-32 billion per year. Hypotheses and themes of CRISP2 are: 1.) Heterogeneous underlying pathogenic mechanisms yield variable clinical phenotypic manifestations; 2.) Comorbidity of sinus disease and lung disease tracks with selected molecular endotypes; 3.) There are profound differences between mechanisms and manifestations of CRS in men and women; 4.) Pathogenic mechanisms of CRSsNP, the more prevalent form of disease, have not been well studied; 5.) There is a significant need to study CRS in primary care populations; 6.) New assays are needed to evaluate molecular endotypes in an outpatient setting. This grant addresses all of these hypotheses and themes. Relating molecular endotypes to clinical manifestations, natural history, comorbidity and outcomes of disease is an overarching goal of this program. Three projects and two cores (Administrative Core A and Clinical, Laboratory and Data Management Core B) comprise the CRISP2 program. The three main project main aims are: Project 1-To study the mechanisms of epithelial barrier dysfunction and tissue hyperplasia in CRS. Project 1 will use a novel microparticle (MP) based assay of epithelial differentiation and will assay components of the coagulation and fibrinolytic systems to test the hypothesis that fibrin deposition, barrier dysfunction and epithelial mesenchymal transition (EMT) play important pathogenic roles in CRS. These responses will be related to immunological endotypes, clinical phenotypes, comorbidity and clinical outcomes. Project 2-To dissect molecular endotypes and relate them to manifestations of CRS. Project 2 will test the hypothesis that inflammation in CRS is heterogeneous and that inflammatory endotypes control clinical phenotypes of CRS. Preliminary results implicate select endotypes as inducers of certain symptom constellations and have led to hypotheses about the cells and molecules that drive the main immunological endotypes, type 1, 2 and 3. Both Project 1 and Project 2 will utilize large sample sets from patients at both Geisinger (Project 3) and NU (Core B). Project 3-To use population-based CRS epidemiology to evaluate sex differences, natural history, and long-term outcomes based on clinically-defined phenotypes and biologically- based endotypes. Large retrospective cohort and longitudinal epidemiological studies proposed include an ongoing study of nearly 8000 study subjects; an EHR-based retrospective study of 10,000 patients and 20,000 controls; a longitudinal study of 450 subjects; and case-control studies of risk factors for bronchiectasis.